The nucleus measures shape changes for cellular proprioception to control dynamic cell behavior

The physical microenvironment regulates cell behavior during tissue development and homeostasis. How single cells decode information about their geometrical shape under mechanical stress and physical space constraints within tissues remains largely unknown. Here, using a zebrafish model, we show that the nucleus, the biggest cellular organelle, functions as an elastic deformation gauge that enables cells to measure cell shape deformations. Inner nuclear membrane unfolding upon nucleus stretching provides physical information on cellular shape changes and adaptively activates a calcium-dependent mechanotransduction pathway, controlling actomyosin contractility and migration plasticity. Our data support that the nucleus establishes a functional module for cellular proprioception that enables cells to sense shape variations for adapting cellular behavior to their microenvironment. Funding: V.V. acknowledges support from the ICFOstepstone PhD Programme funded by the European Union’s Horizon 2020 research and innovation program under Marie Skłodowska-Curie grant agreement 665884. F.P. and Q.T.-R. acknowledge grants funded by Ministerio de Ciencia, Innovación y Universidades and Fondo Social Europeo (FSE) (BES2017-080523-SO, PRE2018-084393). M.A.V. acknowledges support from the Spanish Ministry of Science, Education and Universities through grant RTI2018-099718-B-100 and an institutional “Maria de Maeztu Programme” for Units of Excellence in R&D (CEX2018-000792-M) and FEDER funds.S.W. and M.K. acknowledge support from the Spanish Ministry of Economy and Competitiveness through the Severo Ochoa program for Centres of Excellence in R&D (CEX2019-000910-S), from Fundació Privada Cellex, Fundación Mig-Puig, and from Generalitat de Catalunya through the CERCA program and LaserLab (654148). M.K. acknowledges support through Spanish Ministry of Economy and Competitiveness (RYC-2015-17935, EQC2018-005048-P, AEI-010500-2018-228, and PGC2018-097882-A-I00),Generalitat de Catalunya (2017 SGR 1012), the ERC (715243), and the HFSPO (CDA00023/2018). S.W. acknowledges support through the Spanish Ministry of Economy and Competitiveness via MINECO’s Plan Nacional (PGC2018-098532-A-I00). V.R. acknowledges support from the Spanish Ministry of Science and Innovation to the EMBL partnership, the Centro de Excelencia Severo Ochoa, the CERCA Programme/Generalitat de Catalunya, and the MINECO’s Plan Nacional (BFU2017-86296-P)